Type 1 diabetes (T1D) develops when the insulin-secreting 2 cells in the pancreas are depleted by an autoimmune process of unknown origin. Development of effective preventive therapies for T1D could be enhanced by a better understanding of the underlying disease mechanism, particularly events occurring during the extended pre-clinical period. Such considerations have motivated our studies over the last 15 years, supported largely by this single grant, directed toward identifying the genetic risk factors that might have predictive value and/or provide novel insights into disease etiology and targets for preventive therapy. Over the current cycle of this grant we have continued to pursue linkage studies in T1D but, with the advent of new genomics tools, have shifted our primary efforts toward association-based studies and functional characterization of loci identified by such studies. We tested for association of a number of candidate genes with T1D. For one of these genes, PTPN22, we extended these studies to identify phenotypes in T1D patients. We also completed the largest genome-wide scan for linkage in T1D families (N=2,496) to date, identifying a novel T1D risk locus via family-based association testing in the process. We have also completed a genome-wide association scan (GWAS) of T1D cases and controls which we combined with data from prior GWAS studies by the GoKinD and WTCCC (a total of 7,514 cases and 9,045 controls). The results of this meta-analysis more than doubles the number of established and replicated genomic regions containing T1D risk loci (N = 42). Among the numerous genomic regions identified in this study as associated with T1D we have chosen to focus our new studies on three, 1p13.2, 12q24.12 and 21q22.3, containing the candidate genes PTPN22, UBASH3A, PTPN11 and LNK, which we hypothesize may increase risk for T1D by modulating intracellular signaling from the TCR. In our first two specific aims, we will characterize genetic variation in the 12q24.12 and 21q22.3 regions by re-sequencing and fine-mapping with single nucleotide polymorphisms (SNPs). In our third specific aim, we will investigate the mechanism of action of risk variants at all of these loci, testing both the cellular effects of individual variants transfected into cell lines, and the broader phenotypic consequences in T1D patients and controls. Our success at identifying T1D risk loci during the previous funding cycle allows us to move away from efforts directed at simply enumerating and identifying the number of loci that contribute to T1D and towards mechanistic studies directed at understanding how these loci predispose individuals to the development of T1D. Identification and characterization of the risk variants at these loci, as proposed here, will provide novel insights into T1D pathology and may provide new predictive tools or targets for therapy in T1D.